The high-affinity IgE receptor (FcεRI) blocks apoptosis in normal human monocytes

Monocytes have a limited life span, and their homeostasis is regulated by programmed cell death in vivo (1, 2). Human monocytes cultured in the absence of appropriate exogenous stimuli undergo apoptosis that is enhanced by serum removal (3). The onset of apoptosis can be prevented by adding activating factors such as LPS, TNF-α, IL-1β, and CD40 ligand; and monocytes receiving such signals differentiate into macrophages or dendritic cells (DC) (1–5). These findings suggest that monocytes/macrophages activated in inflamed tissue have a prolonged survival and contribute to the establishment of chronic inflammation (1, 6). Indeed, monocytes from patients with chronic atopic dermatitis (AD) show a significantly lower apoptosis rate in vitro than those from normal individuals (7). The high-affinity IgE receptor (FcεRI) has recently been identified on monocytes from both atopic donors and healthy individuals, and it is considered to play a pivotal role in atopic disorders and host defense by mediating antigen presentation to T cells (8–11). FcεRI expressed on monocytes and other antigen-presenting cells consists of an IgE-binding α-chain (FcεRIα) and two γ-chains (FcεRIγ) (8, 12–14). The cytoplasmic domain of FcεRIγ exhibits a consensus motif, the immunoreceptor tyrosine activation motif, which is crucial for the initiation of the activation cascade triggered by receptor ligation (15). Aggregation of FcεRI on monocytes induces Ca2+ mobilization and production of proinflammatory cytokines by monocytes (16–18). The signals mediated by FcεRI may therefore prolong the survival of monocytes, thereby contributing to the establishment of chronic allergic inflammation. In the present study, we show that FcεRI initiates signals, including Bcl-2 and Bcl-xL expression, which prevent apoptosis of normal monocytes. In addition to these direct effects of FcεRI ligation, cytokines like TNFα, produced upon activation by monocytes, prolonged their survival in an autocrine and paracrine fashion.